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EP-3468946-B1 - CO-CRYSTALS OF LITHIUM BENZOATE AND USES THEREOF

EP3468946B1EP 3468946 B1EP3468946 B1EP 3468946B1EP-3468946-B1

Inventors

  • TSAI, GUOCHUAN EMIL
  • WANG, CHING-CHENG
  • HSIEH, Tien-Lan
  • LO, Yuan-Chun

Dates

Publication Date
20260513
Application Date
20170613

Claims (13)

  1. A co-crystal of a lithium benzoate compound and a co-former, wherein the co-former is a compound of Formula ( I ): in which L is alkyl, C=C, C=C-C=C, C≡C, or absent; A is alkyl, aryl, or heteroaryl; X=O; and provided that when L is absent, A is pyridyl.
  2. The co-crystal of claim 1, wherein the lithium benzoate compound and the co-former exist in the co-crystal in a molecular ratio ranging from 1:10 to 10:1.
  3. The co-crystal of claim 1 or claim 2, wherein L is C=C or C=C-C=C, and A is C 1 -C 6 alkyl, aryl, or heteroaryl.
  4. The co-crystal of claim 3, wherein L is C=C-C=C, A is methyl.
  5. The co-crystal of claim 4, wherein the lithium benzoate compound and the co-former exist in the co-crystal in a molecular ratio of 1:2, and optionally wherein the co-crystal has a powder X-ray diffraction pattern comprising characteristic peaks at a reflection angle 2θ of 6.0, 6.7, 11.0, 11.4, 13.0, 13.3, 16.1, 16.7, 17.5, 18.2, 18.5, 20.5, 21.2, 22.4, 22.8, 23.5, 24.2, 24.8, 25.2, 26.8, and 27.8.
  6. The co-crystal of claim 3, wherein L is C=C, A is phenyl.
  7. The co-crystal of claim 6, wherein the lithium benzoate compound and the co-former exist in the co-crystal in a molecular ratio of 1:1, and optionally wherein the co-crystal has a powder X-ray diffraction pattern comprising characteristic peaks at a reflection angle 2θ of 5.2, 7.1, 7.5, 8.0, 10.2, 12.8, 13.9, 14.5, 16.2, 17.2, 17.6, 18.5, 20.7, 21.2, 22.1, 23.0, 23.8, 24.7, 25.4, 25.8, 26.6, 27.2, 27.8, 29.1, 30.1, 30.9, 31.3, and 33.6, and an endothermic peak corresponding to the melting point of 188 °C.
  8. The co-crystal of claim 1, wherein L is absent, A is pyridyl.
  9. The co-crystal of claim 8, wherein the lithium benzoate compound and the co-former exist in the co-crystal in the molecular ratio of 1:1, and optionally wherein the co-crystal has a powder X-ray diffraction pattern comprising characteristic peaks at a reflection angle 2θ of 6.5, 11.1, 13.1, 15.5, 16.7, 17.5, 18.4, 19.7, 20.3, 20.7, 21.2, 21.6, 22.3, 22.8, 24.4, 24.8, 25.9, 26.9, 28.0, 28.7, 29.2, 30.0, 30.6, 31.6, 32.3, 33.6, 34.1, 35.8, 36.3, 37.2, 38.3, 39.1, 39.9, 41.2, 41.8 and 42.8, and an endothermic peak corresponding to the melting point of 161 °C.
  10. A composition, comprising an effective amount of a co-crystal of any one of claims 1-9 and a carrier, optionally wherein the composition is a pharmaceutical composition, a nutraceutical composition, a health food, or a medical food.
  11. A co-crystal of any one of claims 1-9 or a composition of claim 10 for use in treating or reducing the risk for a neuropsychiatric, wherein the neuropsychiatric disorder preferably is selected from the group consisting of schizophrenia, psychotic disorders, Alzheimer's disease, dementia, mild cognitive impairment, benign forgetfulness, closed head injury, autistic spectrum disorder, Asperger's disorder, attention deficit hyperactivity disorders, obsessive compulsive disorder, tic disorders, childhood learning disorders, premenstrual syndrome, depressions, bipolar disorders, anxiety disorders, post-traumatic stress disorder, chronic pain, eating disorders, addiction disorders, personality disorders, Parkinson's disorder, Huntington's disorder and amyotrophic lateral sclerosis.
  12. A method for preparing a co-crystal of any one of claims 1-9, the method comprising: (i) mixing the lithium benzoate compound and the co-former in a solvent at a temperature of 40-110 °C to form a saturated solution, wherein the lithium benzoate compound and the co-former are at a molar ratio of 1:10 to 10:1; (ii) heating and stirring the solution at a temperature of 70-150 °C to allow formation of the co-crystal; and collecting the co-crystal formed in (ii), optionally wherein step (i) is performed by adding the solvent in a dropwise manner into the lithium benzoate compound and co-former, and stirring the mixture thus formed to allow dissolution of the lithium benzoate compound and co-former in the solvent.
  13. A method for preparing a co-crystal of any one of claims 1-9, the method comprising: providing a co-crystal of any one of claims 1-9, (i) dissolving the co-crystal in a solvent at a temperature ranging from 35-100 °C to form a solution; (ii) stirring the solution at a temperature of 40-110 °C for a first period to allow formation of the co-crystal; wherein the first period is 1-10 days; and (iii) collecting the co-crystal, optionally wherein the method further comprises, following step (ii) before step (iii), stirring the solution at a temperature of 40-110 °C for a second period, wherein the second period is 1-10 days.

Description

BACKGROUND OF THE INVENTION Co-crystals are a homogeneous multicomponent system including at least one drug substance (i.e., active ingredient) and at least one co-former, which are held together by supramolecular synthons. Pharmaceutical co-crystals have attracted significant interest due to the co-crystals' contribution to potential advantageous physicochemical properties of the drug substance, for example, improved solubility, dissolution rate, bioavailability, physical and/or chemical stability, flowability, hygroscopicity, processability, etc. In co-crystal development, suitable co-formers for making pharmaceutical co-crystals of a particular drug substance are typically identified by approaches based on trial and error. Thus, the selection of suitable co-formers for a drug substance and the ratio between the drug substance and the co-former to produce desirable pharmaceutical co-crystals, as well as methods for making such, are the main challenges for producing pharmaceutical co-crystals for a particular drug substance. International patent application WO 2014/172650 discloses co-crystal of lithium benzoate and proline. SUMMARY OF THE INVENTION The present disclosure is based on, at least in part, the identification of suitable co-formers (e.g., sorbic acid, trans-cinnamic acid, and nicotinic acid) for making desirable co-crystals of lithium benzoate, suitable ratios between the co-former and lithium benzoate, and the development of suitable methods for preparing the desirable co-crystals described herein. Such lithium benzoate co-crystals are expected to show advantageous properties, including improved properties such as bioavailability and hygroscopicity. Accordingly, provided herein are co-crystals of a lithium benzoate compound and a co-former, wherein the co-former is a compound of Formula (I) as described herein, compositions comprising such, methods of making such, and uses of the co-crystals for treating and/or reducing the risk for a neuropsychiatric disorder (e.g., schizophrenia, psychotic disorders, depression, pain, or Alzheimer's disease). The invention is as defined in the appended claims. In one aspect, the present disclosure provides a co-crystal of a lithium benzoate compound (e.g., lithium benzoate) and a co-former, wherein the co-former is a compound of Formula (I): in which L is alkyl, C=C, C=C-C=C, C≡C, or absent;A is alkyl, aryl, or heteroaryl; andX=O;provided that when L is absent, A is pyridyl. In some embodiments, the lithium benzoate compound and the co-former exist in the co-crystal in a molecular ratio ranging from 1:10 to 10:1. In some embodiments, L is C=C or C=C-C=C, and A is C1-C6 alkyl, aryl, or heteroaryl. In some embodiments, L is C=C-C=C, A is methyl. In some such embodiments, the lithium benzoate compound and the co-former exist in the co-crystal in a molecular ratio of 1:2. The co-crystal may have a powder X-ray diffraction pattern comprising characteristic peaks at a reflection angle 2θ of 6.0, 6.7, 11.0, 11.4, 13.0, 13.3, 16.1, 16.7, 17.5, 18.2, 18.5, 20.5, 21.2, 22.4, 22.8, 23.5, 24.2, 24.8, 25.2, 26.8, and 27.8. In some embodiments, L is C=C, A is phenyl. In some such embodiments, the lithium benzoate compound and the co-former exist in the co-crystal in a molecular ratio of 1:1, and optionally wherein the co-crystal has a powder X-ray diffraction pattern comprising characteristic peaks at a reflection angle 2θ of 5.2, 7.1, 7.5, 8.0, 10.2, 12.8, 13.9, 14.5, 16.2, 17.2, 17.6, 18.5, 20.7, 21.2, 22.1, 23.0, 23.8, 24.7, 25.4, 25.8, 26.6, 27.2, 27.8, 29.1, 30.1, 30.9, 31.3, and 33.6, and an endothermic peak corresponding to the melting point of 188 °C. In some embodiments, L is absent, A is pyridyl. In some such embodiments, the lithium benzoate compound and the co-former exist in the co-crystal in the molecular ratio of 1:1, and optionally wherein the co-crystal has a powder X-ray diffraction pattern comprising characteristic peaks at a reflection angle 2θ of 6.5, 11.1, 13.1, 15.5, 16.7, 17.5, 18.4, 19.7, 20.3, 20.7, 21.2, 21.6, 22.3, 22.8, 24.4, 24.8, 25.9, 26.9, 28.0, 28.7, 29.2, 30.0, 30.6, 31.6, 32.3, 33.6, 34.1, 35.8, 36.3, 37.2, 38.3, 39.1, 39.9, 41.2, 41.8 and 42.8, and an endothermic peak corresponding to the melting point of 161 °C. In another aspect, the present disclosure provides a composition, comprising an effective amount of a co-crystal as disclosed herein and a carrier, optionally wherein the composition is a pharmaceutical composition, a nutraceutical composition, a health food, or a medical food. In another aspect, the present disclosure provides a co-crystal as disclosed herein or a composition as disclosed herein for use in treating or reducing the risk for a neuropsychiatric disorder, wherein the neuropsychiatric disorder preferably is selected from the group consisting of schizophrenia, psychotic disorders, Alzheimer's disease, dementia, mild cognitive impairment, benign forgetfulness, closed head injury, autistic spectrum disorder, Asperge